The Open Drug Discovery Journal, 2010, 2, 55-63 55 Open Access TRPS and Migraine Romina Nassini*, Francesco De Cesaris, Pamela Pedretti and Pierangelo Geppetti

Headache Center, University Hospital Careggi and Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy

Abstract: Migraine is a highly prevalent, disabling neurovascular disorder characterized by a combination of headache, nausea and altered sensory processing such as photophobia. Migraine has a strong genetic background but the molecular pathways that result in a migraine attack, and the role of various triggers, are poorly understood. The throbbing and pulsating pain associated with the headache phase of migraine attack implies an important role for the nociceptive activation of trigeminal intracranial afferents that contain calcitonin gene-related peptide (CGRP). Neurogenic inflammation triggered by the release of CGRP is now recognized as a significant underlying event in migraine. Indeed, CGRP receptor antagonists, the so-called “gepants”, have already proved effective in clinical trials as novel, migraine- specific drugs. An alternative therapeutic approach is the modulation of CGRP release. As potential targets, the transient receptor potential (TRP) channels expressed by a subpopulation of CGRP-containing nociceptive primary sensory neurons are gaining increasing prominence, principally because of the recent discovery of a variety of endogenous and exogenous TRP agonists known to induce migraine attack as well as their emerging role in neuropeptide release. The present review focuses on the potential role of the different TRP channels, especially TRPV1, in the migraine mechanism. Keywords: TRP channel, TRPV1, migraine, capsaicin, CGRP, neurogenic inflammation, clinical trials, heat, neuropeptides, geptins.

INTRODUCTION the disorder. There is growing evidence that the initiating event (though influenced by several contributing factors such Migraine is a common, disabling and economically as stress, environmental agents or hormones) occurs in the costly [1, 2] neurovascular disorder that affects a significant central nervous system (CNS) and somehow involves portion of the population, an estimated 13 million trigeminal neurons [4, 7]. Americans. Underlying migraine are neurovascular events that result in the dilatation of blood vessels and subsequent In recent years, the hypothesis that the release of nerve activation and pain [3]. Disability due to migraine is calcitonin gene-related peptide (CGRP) from sensory severe. Although migraine involves patients from infancy neurons stimulates sensory nerve transmission and dilates through senescence, it is especially prevalent among women cranial blood vessels has gained experimental support [8], between the ages of 35 and 45 years, with one in five suggesting a major role of CGRP in the pathogenesis of individuals reporting one or more migraine headaches per migraine. In this perspective, CGRP receptor antagonists year in this age group. Migraine care is complicated by the have become attractive as potential migraine-specific drugs. fact that underlying triggers and pathways are poorly Moreover, it has been demonstrated that other brain regions understood. Genetic abnormalities may initiate the alteration with enriched CGRP receptor expression, such as the of the response threshold to migraine-specific triggers in the hypothalamus, are activated during spontaneous migraine brain, but the specific gene(s) involved have not yet been attacks [9]. The first experimental observations that CGRP determined [4]. The migraine attack can be precipitated by (8–37), a truncated form of CGRP [10], behaved as a an extraordinary variety of stimuli, including psychological competitive and selective antagonist of the biological effects stress factors, excessive ingestion of alcoholic beverages, of CGRP, including smooth muscle relaxation, were not menstrual cycle, and changes in barometric pressure, anti- pursued, mainly because of the short biological half-life of angina medicines, sleep deprivation, and other factors [5, 6]. this peptide. More recently, the inhibition of CGRP receptors The lack of knowledge about the pathways underlying with two chemically unrelated CGRP receptor antagonists, migraine attack is one of the major obstacles to the discovery telcagepant and olcegepant (collectively referred to as of better and safer drugs. Uncertainty also exists regarding “gepants”) [11, 12], has been successfully used to treat acute the precise site of action and molecular targets of the various migraine [13-15]. drugs used for both prophylaxis and symptomatic relief of CGRP is contained in neurons of the central and migraine attack. However, in recent years much progress has peripheral nervous system. In the periphery, except for been made to better understand the underlying mechanism of intrinsic neurons of the gastrointestinal tract, CGRP is strictly confined to a subpopulation of somatosensory neurons with cell bodies located in the dorsal root (DRG), *Address correspondence to this author at the Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139 vagal (VG) and trigeminal (TG) ganglia. The release of Florence, Italy; Tel: +39 055 427 1417; Fax: +39 055 427 1280; sensory neuropeptides, including CGRP, undergoes fine E-mail: [email protected] tuning by a series of mediators and agents that act at

1877-3818/10 2010 Bentham Open 56 The Open Drug Discovery Journal, 2010, Volume 2 Nassini et al. prejunctional receptors/channels on sensory nerve terminals. symptoms of migraine attack. A considerable number of A wide array of G protein-coupled receptors are involved in animal and human studies have been carried out to better this process, including those for bradykinin, prostanoids, understand the physiology and pharmacology of the sensory opioids, 5-hydroxytryptamine (5-HT1 receptor), histamine innervation of the dura mater and cranial vessels. Evidence (H3 receptor), neuropeptide Y, somatostatin, vasoactive obtained in experimental animals suggests that the migraine intestinal polypeptide (VIP), purines and galanin. One of the aura is the clinical manifestation of a cortical spreading major mechanisms that promotes CGRP release from depression (CSD) [24, 25]. It has been proposed that the sensory neurons is the activation of members of the transient neural changes caused by the slow depolarizing wave of receptor potential (TRP) family of channels, in particular CSD eventually result in the painful symptoms associated TRPV1 (Founding member of the Transient Receptor with vasodilatation of the cranial blood vessels and other Potential Vanilloid family). The present review focuses on phenomena of the migraine attack [4]. However, while the distribution and activation mechanisms of the different tonabersat, a drug specifically developed to block CSD, did TRP channels expressed by subsets of trigeminal primary abolish the aura, it failed to prevent the headache of migraine sensory neurons, and discusses the potential of this receptor attack, in either an acute or a chronic setting [26-28]. This family in migraine mechanisms. finding indicates that CSD and the resulting aura are epiphenomena, but not the cause of the pain of migraine PRIMARY SENSORY NEURONS AND NEUROGENIC attack. INFLAMMATION: ROLE IN MIGRAINE In experimental animals, particularly rodents, stimulation More than 70 years ago, Sir Thomas Lewis, in his of a subset of peptidergic somatosensory neurons leads to the pioneering studies [16], precisely defined the dual release of various neuropeptides, specifically CGRP and the 'nocifensor' role of a subset of primary sensory neurons. One tachykinins SP and neurokinin A (NKA). Activation of segment of the widely branching sensory fiber network of CGRP receptors and tachykinin (NK1, NK2 and NK3) this neuron responds to the injury and generates action receptors located on effector cells at the peripheral level potentials which are carried antidromically to collateral causes a series of inflammatory responses, collectively branches, where these branches release a chemical substance referred to as ‘neurogenic inflammation’ [17]. This term that causes a flare response and increases the sensitivity of refers to a cascade of events that occur mainly, but not other sensory fibers responsible for pain. It has been exclusively, at the perivascular level. Indeed, CGRP-, SP-, proposed that the neurons which mediate these responses and NKA-release induce vasodilatation in arterial vessels, belong to a previously unrecognized subgroup, and termed and plasma protein extravasation and leukocyte adhesion to ‘nocifensors’ because of their dual function. The first the vascular endothelium of postcapillary venules [17]. function of these nocifensors is to sense nociceptive/pain These two latter responses are mediated by NK1 receptor stimuli. The second is to promote a first line of defense, activation on endothelial cells, which results in a calcium- mediated through neurovascular responses, which includes dependent activation of intracellular contractile elements, arterial vasodilatation, plasma protein extravasation, and leading to the opening of gaps between cells and the other responses. All these responses are associated with the development of inflammatory edema. In the dura mater, capacity to release neuropeptides from peripheral terminals neurogenic plasma extravasation mediated by NK1 receptors of primary sensory neurons. There is now substantial has been initially proposed as the main mechanism by which evidence to suggest that a neurogenic component of the trigeminovascular system contributes to the pathogenesis inflammation exists whose main features have been of the migraine attack [20]. Unfortunately, this exciting described in details previously [17, 18]. hypothesis has not been supported by successful clinical In laboratory animals, neurogenic inflammation has been studies: selective and high affinity NK1 receptor blockers well documented in multiple tissues and organs, and its role did not relieve migraine attacks [29-31]. The negative has been robustly established in relevant models of human evidence from the clinic regarding a role of SP and NK1 diseases. However, the hypothesis that this phenomenon receptors in migraine is in agreement with failure to contributes significantly to human diseases, and in particular demonstrate SP/NKA release from human tissues containing to migraine, is still a matter of debate. However, recent trigeminal nerve endings [32]. However, there is recent clinical trials [19] have given credence to this hypothesis preclinical and clinical evidence pointing to the contribution with neurochemical and pharmacological data supporting the of CGRP in migraine. This neuropeptide, released following key role that neurogenic inflammation plays in the exposure to a large variety of stimuli from terminals of mechanism of migraine [20]. primary sensory neurons, may cause a neurogenic arterial vasodilatation, or other effects relevant for the pathogenesis Cerebral vessels, pial vessels, large venous sinuses and of migraine. In particular, evidence is now emerging for a dura mater are surrounded by a dense plexus of role of CGRP in the activation and sensitization of unmyelinated fibers that arise from the ophthalmic division nociceptors at the peripheral, and, perhaps, at the central of the trigeminal ganglion. The trigeminal nerve also level. innervates extracranial tissues, including vessels. Altogether, this dense network of mainly perivascular fibers comprises CGRP is synthesized and released from somatosensory the so called trigemino-vascular system [21]. Trigeminal neurons with small cell bodies and fibers that are fibers, arising from neurons in the trigeminal ganglion, unmyelinated (C-fibers) or thinly myelinated (A
-fibers). contain CGRP and substance P (SP) [22]. The stimulation of This extensive network of sensory nerves, found in virtually trigeminal ganglia/nerve is considered a necessary step for all tissue and organs, suggests a potential role for CGRP in the process that underlies pain [23] and the associated diverse physiologic and pathophysiologic processes. The remarkable vasodilatation elicited by CGRP in the cerebral, TRPS and Migraine The Open Drug Discovery Journal, 2010, Volume 2 57 coronary, and peripheral vasculature has led to its therapeutic mechanical stimuli associated with inflammatory and evaluation in the treatment of cerebral vasospasm following neuropathic pain. subarachnoid hemorrhage, stable angina, and Raynaud's TRPV1 is activated by three main pain-producing phenomenon [33]. The inotropic action and coronary stimuli: (1) vanilloid compounds (capsaicin, resiniferatoxin), vasodilatation have also led to a potential beneficial use of (2) noxious heat (
43 °C), and (3) low pH (<5.9) [47, 48]. In CGRP in congestive heart failure [34, 35]. CGRP interacts addition, a series of endogenous molecules of lipid nature with specific G protein-coupled receptors to produce a have been shown to activate the TRPV1 [48-51]. However, vasodilatory effect which is more potent than that observed the physiologic relevance of these molecules has been with other classical vasodilators, including prostaglandins, questioned because it is unclear if their tissue concentrations acetylcholine, adenosine, and SP. Except for a few vascular found under either physiological or pathological conditions preparations, including the rat aorta and the human internal are sufficient to activate TRPV1. In addition to TRPV1 mammary artery, where the relaxation of CGRP depends on receptor, additional heat-sensitive TRPs (“thermoTRPs”) the presence of an intact endothelium and is attenuated by have been described in TRPV1-expressing primary sensory inhibitors of nitric oxide (NO) synthase [36-38], the neurons of the TG, VG and DRG, including TRPV2, relaxation induced by CGRP is mediated by an endothelium- TRPV3, TRPV4, and TRPA1. TRPM8, also known as the independent phenomenon. menthol receptor, is expressed by a different TRPV1- Trigeminal sensory nerve fibers that robustly stain with negative neuronal subpopulation. ThermoTRP channels are anti-CGRP antibodies are well represented at the intracranial emerging as sensory transducers that may participate in the and extracranial level [39]. The enriched expression of generation of pain sensations evoked by chemical, thermal CGRP by trigeminal sensory neurons, and its release from and mechanical stimuli. There is also some evidence to these cells, has been demonstrated both in humans and suggest a role for TRPV4 in mechanosensation. However, animal models [40, 41]. Furthermore, recent evidence shows the hallmark of TRP channels is their polymodality. While that in animal models and in man [12] the vasodilatation the precise distribution of each of these channels in sensory induced by depolarizing stimuli was inhibited by a CGRP- neurons is poorly understood, recent work has started to receptor antagonist, indicating that neurogenic vasodilatation provide some clarity. is mediated by the release of CGRP from primary sensory By using radial stretch in combination with live-cell neurons. Moreover, plasma concentrations of CGRP, but not calcium imaging, different mechanosensitive and insensitive of SP, were found to be elevated during spontaneous or sensory neuronal categories were identified [52]. A group of nitroglycerine-provoked attacks of migraine [42] and cluster small-diameter stretch-sensitive cells could be further headache [43]. More importantly, the intravenous infusion of subdivided into (1) a cluster of small-diameter cells sensitive CGRP produced a migraine-like headache [44], and to both hydroxy--sanshool (a two pore K channel intravenous infusion of NO evoked a migraine-like headache antagonist) and the TRPV1 agonist capsaicin, and (2) a with an associated increase in plasma CGRP levels in female cluster comprised of large-diameter cells that respond to migraineurs [45]. Finally, the CGRP plasma levels were hydroxy--sanshool, but not capsaicin. The former neuron more elevated in migraine patients, and changes in plasma type likely corresponds to high threshold nociceptors, and CGRP levels during migraine attacks were related to the the latter to low threshold proprioceptors. Moreover, stretch headache intensity [45]. Not only does it appear that CGRP insensitive neurons fall into two groups of small-diameter release in cranial or systemic circulation is a suitable marker cells; the first group is composed by peptidergic neurons of trigemino-vascular activation in cluster headache and sensitive to capsaicin and to the TRPA1 selective agonist migraine [46], but the positive clinical trials with CGRP mustard oil, and a second group by a small cohort of receptor antagonists also suggest that local CGRP secretion menthol-sensitive cells [52]. Thus, TRPA1-expressing is likely causative factor in migraine and cluster headaches. neurons, which obligatorily co-express TRPV1, are those TRP CHANNELS IN PRIMARY SENSORY NEURONS apparently insensitive to mechanical stimulation which, because they contain neuropeptides, bring about neurogenic The stimulation of a subset of primary sensory neurons at inflammation and neurogenic CGRP-mediated the level of their peripheral terminals is not only associated vasodilatation. (Parenthetically, recent data suggest a role for with the induction of neurogenic inflammation, but also TRPA1 in mechanotransduction.) Finally, a subgroup of results in the transmission of nociceptive, or pain, signals. neurons, which does not contain neuropeptides, is uniquely The neurons, which may mediate both the sensory, afferent sensitive to the excitatory action of menthol and express the response and the ‘local’ efferent effect, are those belonging relatively specific menthol-receptor TRPM8 [53], but not to the sub-category with A and C fibers, and are defined as TRPV1 and/or TRPA1. polymodal nociceptors because they sense thermal, chemical, and high-threshold mechanical stimuli. A subset of The study of peripheral sensory fibers has been these sensory neurons is also uniquely sensitive to capsaicin, facilitated by natural products, such as capsaicin, and these the pungent principle contained in plants of the genus molecules have proven to be exquisite tools to probe the Capsicum. The sensation of burning pain that follows function of primary sensory neurons in a wide array of exposure of peripheral sensory neurons to capsaicin is physiological processes, ranging from pain to neurogenic mediated by TRPV1, the founding member of the Vanilloid inflammation. But, sensory TRP channels are not simply subfamily of TRP ion channels [47]. TRPV1 is a polymodal natural product receptors. They are molecular sensors of an sensor which, in mammals, has been proposed to play a array of modalities (temperature, protein kinase activity, crucial role in the hypersensitivity to thermal, chemical and phospholipids, osmolarity and pH), which, leading to a common transduction process, elicit somatosensory 58 The Open Drug Discovery Journal, 2010, Volume 2 Nassini et al. responses. Therefore, the identification of TRP channels as exposure of mucosal surfaces or wounds to alcoholic the molecular transducers and integrators of a broad range of tinctures causes burning pain has remained without an sensory modalities, best exemplified by TRPV1, has explanation until the observation that ethanol excites provided new insights into the physiological role of sensory TRPV1-expressing rat sensory neurons [69]. TRPV1, usually nerve fibers. stimulated at 42 °C, is activated by lower temperatures in the presence of ethanol, such as the physiological temperature of ACTIVATION MECHANISMS OF TRP CHANNELS 37 °C, because ethanol lowers the threshold temperature for EXPRESSED IN TRIGEMINAL SENSORY NEURONS TRPV1 activation by about 8 °C [69]. In the presence of Of the five heat-sensitive members of the TRP family ethanol, the effects of TRPV1 agonists, including anand- [54, 55] that are co-expressed with TRPV1 in primary amide and protons, are markedly potentiated [69]. sensory neurons, three (TRPV2, TRPV3 and TRPV4) are In the last few years, the role of the TRPA1 channel on gated by warm, non-noxious and noxious temperatures and primary sensory neurons has also been better defined. small reductions in tonicity. In particular, TRPV4 activation Shortly after the identification of TRPA1 receptor in human has been associated with the release of neuropeptides and pulmonary fibroblasts [70] and in hair cells of the auditory resulting neurogenic inflammation in peripheral tissues [56]. system [71], abundant expression of TRPA1 was recognized A more detailed pharmacological characterization of in a subpopulation of peptidergic primary sensory neurons TRPV2, TRPV3 and TRPV4 has up to now been limited by with C and A fibers of the DRG, VG and TG that co- the absence of selective activating and blocking compounds express TRPV1 [72]. TRPA1-expressing neurons contain of these TRP subtypes. In particular, the lack of selective and release the neuropeptides CGRP, SP and NKA from antagonists has narrowed the possibility to gain better their terminals, which in peripheral tissues produce knowledge on the role of these channels in health and neurogenic inflammation [17]. Although the TRPA1 channel disease. TRPM8 channels are activated by menthol and has been proposed to be involved in the transduction of moderately low temperature [47, 53, 57-60]. thermal [73] and mechanical [74] stimuli, it is best It is well known that stimulation of TRPV1 by capsaicin characterized as a “chemosensor”, activated in response to produces a burning sensation and releases sensory many chemical agents (a large number produced by plants neuropeptides such as CGRP. Because of the unique and still others synthetic) that, like capsaicin, activate capability of capsaicin to activate and desensitize TRPV1 for peripheral C-fibers, thereby causing acute pain, thermal and decades it has been considered an instrument for better mechanical hyperalgesia, and neurogenic inflammation. understanding the function of a subset of neuropeptide- Icilin, an activator of both TRPM8 and TRPA1 receptors, containing sensory neurons that mediate neurogenic is in fact able to produce cold sensation [53, 60]. In contrast, inflammation, as well as of their role in models of human other chemicals, including isothiocyanates (pungent diseases [17]. In addition to its initial excitatory effect, ingredients of edibles like wasabi, mustard, and horseradish) exposure to high concentrations/doses of capsaicin for a show high selectivity for TRPA1. Cinnamaldehyde prolonged time induces a desensitization of the sensory (contained in cinnamon), allicin and diallyl sulfides (garlic neurons or nerve endings in a time- and concentration/dose- and onions), carvacrol (oregano), and polygodial (water dependent manner, an effect that ultimately results in the pepper and Tasmanian pepper) are TRPA1-stimulating inability of the nerve fibers to evoke pain and neurogenic agents [54, 75]. Robust and conclusive evidence has been inflammation [18, 61]. Moreover, because after capsaicin accumulated in the past 5 years with respect to the ability of application the tissue becomes desensitized and irresponsive TRPA1 to respond to a host of environmental irritants. These to a series of painful stimuli, this procedure has been used to include acrolein (2-propenal), a highly reactive
,- successfully treat various painful conditions [62]. unsaturated aldehyde, produced endogenously or present in TRPV1 receptor activation is not only mediated by tear gas, vehicle exhaust, or smoke from burning vegetation exogenous xenobiotics, such as capsaicin, but also by a (i.e., forest fires and cigarettes) [76] and other volatile series of endogenous agents, including low extracellular pH, irritants such as and formalin [77] and isocyanates [78]. anandamide, N-arachydonoil-dopamine, ecosanoids and TRPA1 has been also recognized as the target of a series of other agents [48-51]. The major pro-inflammatory peptide endogenous
,ß-unsaturated aldehydes, which are produced bradykinin, indirectly (via activation of the B2 receptor) by lipid peroxidation in response to oxidative stress at sites sensitizes TRPV1 by diverse intracellular mechanisms [63, of inflammation and tissue injury [76, 79, 80]. These 64]. Regulation of TRPV1 channels by a diverse array of aldehydes include 4-hydroxy-2-nonenal (HNE) which is signaling underlines the role of sensitization in the produced by peroxidation of omega 6-polyunsaturated fatty modulation of the sensory and proinflammatory functions of acids, such as linoleic acid and arachidonic acid [81, 82] or nociceptors. The finding that PAR-2 stimulation up-regulates 4-oxononenal [83]. Moreover, new reactive TRPA1 agonists the function of TRPV1 through a Protein Kinase C (PKC) - have been discovered at a breathtaking pace, suggesting that, dependent mechanism adds PAR-2 to the list of G protein- given appropriate conditions, almost all oxidizing or coupled receptors that, by regulating TRPV1, orchestrate the electrophilic chemicals will affect TRPA1 function. These neural components of the inflammatory response [65]. include the reactive oxygen species (ROS) hydrogen 2- Sensitization of TRPV1 by PKC and cAMP-dependent peroxide (H2O2) [78, 84, 85], superoxide (O ), hypochlorite protein kinase A (PKA) pathways seems to be (ClO-) [86] and the reactive nitrative species (RNS) promiscuously used by different stimuli, including capsaicin, peroxynitrite (ONOO-) [85]. Also, nitrooleic acid, a anandamide, heat and protons [63,66-68], but it is not unique byproduct of nitrative stress, is a TRPA1 activator [87]. to endogenously generated agents. The common notion that During inflammation, ROS are generated in abundance. Exposure of cellular membranes to ROS causes membrane TRPS and Migraine The Open Drug Discovery Journal, 2010, Volume 2 59 lipid peroxidation, producing electrophilic reactive mediators derivatives and triptans also reduce neuronal activity at the such as cyclopentenone prostaglandins and isoprostanes, all trigeminocervical complex [95] and thalamic level [96]. compounds that have been recognized as TRPA1 agonists Triptans, because of their superior tolerability, are the most [88, 89]. Thus, byproducts of oxidative/nitrative stress effective medication chosen for severe migraine attacks converge on TRPA1 to alert the sensory system of the replacing ergotamine in most cases [97]. However, the presence of inflammation or tissue damage. Similar to vasoconstrictive effect of triptans precludes their use in TRPV1, TRPA1 is sensitized by a number of patients with cardiovascular disease [98]. proinflammatory stimuli. To develop a therapy aimed at reducing attack frequency Despite their different structures, all these stimuli are and severity of migraine in daily practice, new unified in their ability to form covalent adduct with the thiol pharmacological and interventional therapies treatment group, a moiety that confers them the ability to activate strategies are being investigated. A major breakthrough in TRPA1 receptor. Several known TRPA1 agonists, including the field was the discovery of the peptoid CGRP receptor acrolein and other
,ß-unsaturated aldehydes, possess an antagonist olcegepant [99], which, with high affinity and electrophilic carbon or sulphur atom that is subject to selectivity, inhibited neurogenic vasodilatation in various nucleophilic attack (Michael addition) [90] by cysteine, experimental animals and in humans [19]. More recently, the lysine or histidine of TRPA1. Mutagenesis studies have discovery of the orally available antagonist, telcagepant clarified that such reactivity promotes channel gating [100], has been reported, a compound which binds the through covalent modification of residues within the CGRP receptor with high affinity and inhibits capsaicin- cytoplasmic N-terminal domain of the channel [80, 91, 92]. induced increases in forearm dermal blood flow in rhesus monkeys [12]. Telcagepant was able to abort acute migraine RECENT ADVANCES IN MIGRAINE TREATMENT: with significant effect at two hours [14]. Both drugs have CONTRIBUTION OF TRPV1/TRPA1 RECEPTORS AS been shown to reduce the pain and the associated symptoms POTENTIAL THERAPEUTICAL TARGET of migraine attack with efficacy similar to triptans, but were Migraine is a disorder of the brain characterized by a safer. Moreover, the marked and prolonged efficacy of complex sensory dysfunction. Unfortunately, precise CGRP antagonists might represent a significant advancement mechanisms involved in this neuronal dysfunction are not for those patients who respond poorly to triptans. The well understood. Some studies define a central origin of success obtained in the relief of headache pain and other headache pain [4], whereas others consider the activation and symptoms of the migraine attack with CGRP receptor sensitization of peripheral nociceptors as the starting event of antagonists reinforces a neurally-based approach to migraine. headache pain. More recently, the possibility that reduced In this perspective, the identification of the molecular inhibitory brainstem activity is sufficient to generate pain pathways that cause the release of CGRP from peptidergic from otherwise silent nociceptors has been questioned [7]. sensory neurons is of primary interest. As peptidergic Thus, if peripheral activation and sensitization of cranial trigeminal neurons are labeled as TRPV1- and TRPA1- nociceptors underlies migraine, it becomes important to positive, major attention must be paid to these channel identify the mediators that activate/sensitize perivascular subtypes in order to provide a broader repertoire of migraine- nerve terminals that innervate cerebral, dural, and specific drugs. extracranial arteriole. In the last few decades, increased Many studies have shown the ability of repeated knowledge of the neurobiological and pharmacological intranasal application with topical TRPV1 agonists to components of a subset of trigeminal primary sensory ameliorate migraine attack indicating that TRPV1-positive neurons has provided key information for the development neurons play a significant role in the pathophysiology of of effective molecules that specifically target the activation migraine. Repeated capsaicin application to the nasal mucosa of the trigeminovascular system, and may represent a reduced the headache attacks of both chronic and episodic significant advancement in the treatment of the disease. cluster headache [101, 102]. The contribution of TRP The prevention of migraine is a significant component of channels in triggering migraine attack is shown in recent therapy aimed at reducing the severity and the frequency of studies with ethanol. Alcoholic beverages are known the attack. Substances that have proven beneficial in inducers of migraine attacks and, accordingly, migraineurs migraine include beta-blockers (propranolol), antidepressants do not usually drink alcoholic beverages. However, it is not (amitriptyline), anticonvulsants (valproate, topiramate), known why alcohol precipitates migraine attacks. Our recent calcium channel blockers (flunarizine) and serotonin studies demonstrate that ethanol (1-3% solution) reduces the antagonists (methysergide) [93]. According to the threshold temperature for activation of the TRPV1 by 8 ºC pathophysiological events involved in migraine attack, these (from ~43 to ~35 ºC) [69]. Thus, ethanol enables TRPV1 drugs most probably target the activity of modulatory activation by normal body temperature, thereby producing circuits, as well as the neuronal activity in afferent sensory the well know sensation of burning pain. The observation pathways, such as the trigeminal system [94]. that ethanol stimulates TRPV1 channels and produces a CGRP-dependent vasodilatation of dural blood vessels [103] For severe migraine attacks, treatment with non-specific suggests the ability of alcoholic beverages to trigger the analgesic compounds, such as non steroidal anti- migraine attack. Previous pharmacological findings that low inflammatory drugs (NSAIDS), and more migraine-specific extracellular pH stimulates the TRPV1 [49] have been treatment approaches, such as ergot derivates and triptans, confirmed by genetic studies [48]. Ethanol increases by ~50 which are active at 5-HT receptors, is currently considered 1 times the ability of low pH to activate the TRPV1 [69]. to be the ‘gold-standard’ of care. In addition to their Thus, the TRPV1 sensitizing action of ethanol to the peripheral anti-inflammatory and analgesic effects, ergot excitatory effect of a variety of normal or pathological 60 The Open Drug Discovery Journal, 2010, Volume 2 Nassini et al. stimuli (temperature, pH, anandamide) may contribute to the towards improving migraine therapy. This advancement also CGRP release that precipitates the migraine attack. has an enormous impact on the understanding of the mechanism of the disease, and confirms that better Our recent understanding of the pathways that produce knowledge of the pathophysiological and pharmacological TRP sensitization and hyperactivity may help explain the conflicting clinical evidence regarding the efficacy of aspects of trigeminal primary sensory neurons will accelerate the identification of novel therapeutics to treat migraine and NSAIDs in the treatment of headache syndromes including other primary headaches. Recent clinical data obtained with cluster headache, paroxysmal hemicrania, and acute chemically different CGRP antagonists identifies this migraine attacks. Most cluster headache patients are resistant neuropeptide, selectively released from a subset of to cyclooxygenase inhibitors. Conversely, paroxysmal nociceptive trigeminal nerve fibers co-expressing TRPV1 hemicrania specifically responds to indomethacin, a drug that may also provide some temporary relief during mild and TRPA1, as an important contributing molecule in the mechanism of migraine. Recently, a TRPV1 receptor migraine attacks [104]. Thus, the contribution of classical antagonist (SB-705498) has been tested in migraine. prostaglandins to migraine and other primary headaches such Preclinical data have demonstrated that the inhibition of as paroxysmal hemicrania cannot be negated. There is TRPV1 receptor with this molecule can both prevent and increasing evidence linking the beneficial action of NSAIDs reverse established central sensitization [108]. to TRPV1 and TRPA1. In animal models, TRPV1 expression is plastic and is up-regulated by neurotrophic Moreover, TRPA1 is also emerging as a potential target factors, most notably NGF, during inflammation. In addition, for the treatment of migraine. TRPA1 is expressed by a TRPV1 is sensitized by both NGF and various pro- subset of nociceptive trigeminal nerve fibers that selectively inflammatory mediators [63, 105]. These phenomena may release CGRP upon activation. This release causes also play a role in the pathogenesis of migraine. Indeed, neurogenic vasodilatation. The discovery of exogenous and, prostaglandins (via prostaglandin-activated protein kinase A) more importantly, endogenous activators of this channels have been reported to sensitize TRPV1 [106]. Moreover, low that plays critical roles in inflammation further lend credence extracellular pH, which is often present at the site of to the idea it could be involved in pain pathophysiology in inflammation, was shown to stimulate TRPV1 [48, 49] and general and migraine pathophysiology in specific. It is hoped to induce the release of sensory neuropeptides from the dura that potent, small molecule TRPV1 and/or TRPA1 [107]. Thus, it may be speculated that blockade of TRPV1 antagonists will broaden the therapeutic options in patients activation and/or sensitization by prostaglandins and other who cannot be adequately managed by available agents in inflammatory soup contributes to the beneficial antimigraine medications. effect of NSAIDs in migraine. This model provided the foundation of the clinical trials with the potent, small REFERENCES molecule TRPV1 antagonist SB-705498 in treatment of [1] Lipton, R.B.; Stewart, W.F.; Scher, A.I. Epidemiology and migraine pain [108]. 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Received: January 18, 2010 Revised: March 2, 2010 Accepted: March 10, 2010

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